X marks the spot in autoimmunity.

INTRODUCTION: Autoimmune diseases mostly affect females. Besides hormones, several factors related to chromosome X have been called in action to explain this sex predominance. AREAS COVERED: This paper provides an overview on the role of chromosome X (chrX) in explaining why females have higher susceptibility to autoimmunity. The work outlines some essential concepts regarding chrX inactivation, escape from chrX inactivation and the evolutionary history of chrX. In addition, we will discuss the concept of gene escape in immune cells, with examples related to specific X-linked genes and autoimmune diseases. EXPERT OPINION: There is growing evidence that many genes present on chrX escape inactivation, and some of them have significant immune-mediated functions. In immune cells of female individuals the escape of these genes is not constant, but the knowledge of the mechanisms controlling this plasticity are not completely understood. Future studies aimed at the characterization of these modifications at single-cell resolution, together with conformational 3D studies of the inactive X chromosome, will hopefully help to fill this gap of knowledge.